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The Journal of Clinical Endocrinology & Metabolism 89(11):5429 –5434
Copyright © 2004 by The Endocrine Society
doi: 10.1210/jc.2004-0897
Intramuscular Testosterone Undecanoate:
Pharmacokinetic Aspects of a Novel Testosterone
Formulation during Long-Term Treatment of Men
with Hypogonadism
M. SCHUBERT, T. MINNEMANN, D. HÜBLER, D. ROUSKOVA, A. CHRISTOPH, M. OETTEL,
M. ERNST, U. MELLINGER, W. KRONE, AND F. JOCKENHÖVEL
Klinik II und Poliklinik für Innere Medizin der Universität zu Köln (M.S., T.M., A.C., W.K.), 50931 Köln, Germany;
Jenapharm GmbH & Co. KG (D.H., D.R., M.O., M.E., U.M.), 07745 Jena, Germany; and Evangelisches Krankenhaus Herne
(F.J.), 44623 Herne, Germany
In an open-label, randomized, prospective trial, we investigated pharmacokinetics and several efficacy and safety parameters of a novel, long-acting testosterone (T) undecanoate
(TU) formulation in 40 hypogonadal men (serum testosterone
concentrations < 5 nmol/liter). For the first 30 wk (comparative study), the patients were randomly assigned to receive
either 10 ⴛ 250 mg T enanthate (TE) im every 3 wk (n ⴝ 20) or
3 ⴛ 1000 mg TU im every 6 wk (loading dose) followed by 1 ⴛ
1000 mg after an additional 9 wk (n ⴝ 20). In a follow-up study,
observation continued in those patients who completed the
comparative part and opted for TU treatment (8 ⴛ 1000 mg TU
every 12 wk in former TU patients and 2 ⴛ 1000 mg TU every
8 wk plus 6 ⴛ 1000 mg every 12 wk in former TE patients) for
an additional 20 –21 months. Here we report only the pharmacokinetic aspects of the new TU formulation for the first
approximately 2.5 yr of treatment. At baseline, serum T concentrations did not significantly differ between the two study
groups. In the TE group, mean trough levels of serum T were
always less than 10 nmol/liter before the next injection,
whereas in the TU group, mean trough levels of serum T were
14.1 ⴞ 4.5 nmol/liter after the first two doses (6-wk intervals)
A
NDROGENS PLAY AN essential role in the sexual
differentiation and function in men and are known to
participate in the regulation of bone metabolism, body composition, and hematopoiesis (1). Therefore, androgen replacement therapy in hypogonadal men results in improvement of sexual function as well as increment in bone density,
lean body mass, erythropoiesis, prostate size, and changes in
lipid profiles, as described by several authors (2– 4). Testosterone (T) formulations have been used for replacement therapy in male hypogonadism for over six decades. Because the
number of patients with male hypogonadism is small, the
effort to develop new T formulations has been modest. Subcutaneous implants were developed in the 1940s; T enanthate
(TE) and T cypionate (esters for im injections) were developed in the 1950s; oral T undecanoate (TU) was developed
Abbreviations: DHT, Dihydrotestosterone; E2, estradiol; LOD, limit of
detection; LOQ, limit of quantitation; PSA, prostate-specific antigen; T,
testosterone; TE, testosterone enanthate; TU, testosterone undecanoate.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
and 16.3 ⴞ 5.7 nmol/liter after the 9-wk interval at wk 30. The
mean serum levels of dihydrotestosterone and estradiol also
increased in parallel to the serum T pattern and remained
within the normal range. In the follow-up study, the former TU
patients (n ⴝ 20) received eight TU injections at 12-wk intervals, and the TE patients (n ⴝ 16) switched to TU and initially
received two TU injections at 8-wk intervals (loading) and
continued with six TU injections at 12-wk intervals (maintenance). This regimen resulted in stable mean serum trough
levels of T (ranging from 14.9 ⴞ 5.2 to 16.5 ⴞ 8.0 nmol/liter) and
estradiol (ranging from 98.5 ⴞ 45.2 to 80.4 ⴞ 14.4 pmol/liter).
The present study has shown that 1000 mg TU injected into
male patients with hypogonadism at 12-wk intervals is well
tolerated and leads to T levels within normal ranges, using
four instead of 17 or more TE injections per year. An initial
loading dose of either 3 ⴛ 1000 mg TU every 6 wk at the beginning of hormone substitution or 2 ⴛ 1000 mg TU every 8 wk
after switching from the short-acting TE to TU were found to
be a adequate dosing regimens for starting of treatment with
the long-acting TU preparation. (J Clin Endocrinol Metab 89:
5429 –5434, 2004)
in the 1970s; and transdermal patches were developed in the
1990s (5–7). Although frequently used, most of these formulations have unfavorable pharmacokinetics, resulting in subphysiological, supraphysiological, and/or fluctuating serum
T levels. The widely used TE injections often cause discomfort not only due to fluctuating serum T levels but also
because of frequent injections (5, 6). The more recently developed transdermal patches show better pharmacokinetics
but frequently cause skin irritations (7). Currently, one of the
most used formulations consists of injectable T esters requiring im injections every 2–3 wk. Using this regimen, patients
frequently report mood swings due to high T levels shortly
after the injection and relatively low T levels at the end of
each cycle (5). A considerable improvement is the T gel, with
daily applications resulting in stable T levels over 24 h (8, 9).
Long-acting T preparations may offer a good alternative to
a daily application regimen.
We report here the first direct comparison of a new TU
formulation for im injection vs. a standard treatment with
short-acting TE (two-arm, active treatment-controlled study
of 30 wk; main study) and the first long-term experience with
5429
5430
J Clin Endocrinol Metab, November 2004, 89(11):5429 –5434
TU given at equally extended interinjection intervals (onearm, uncontrolled follow-up study of ⬃92–96 wk). Moreover, this study design provides the first clinical experience
with a direct switch from a standard T therapy using TE to
a new long-acting depot injection of TU according to a systematic regimen of dosing.
TU, having a midchain fatty acid bound in the 17␤-position, is already approved for oral administration. The first
single-dose and multidose pharmacokinetic studies of im TU
in castor oil have been published, demonstrating a possible
injection interval of more than 6 wk (10, 11). These prolonged
intervals make the im injectable TU formulation an attractive
candidate not only for replacement therapy but also for hormonal male contraception.
The active treatment-controlled study aimed to investigate
the efficacy and safety of a dosage regimen of 1000 mg TU
in 4 ml oily solution im at 6-wk intervals (first three doses)
and 9-wk intervals (subsequent doses) vs. 250 mg TE in 1 ml
oily solution im at 3-wk intervals during a 30-wk course of
replacement therapy in men with hypogonadism. The follow-up study provided further information on efficacy and
safety of the TU preparation after long-term administration
over a period of approximately 19 months using a prolonged
(12 wk) interval between the injections. In the main and the
follow-up studies, several parameters of efficacy and safety
were assessed.
Here we report the pharmacokinetic aspects of the new TU
formulation and its effect on the serum levels of T, dihydrotestosterone (DHT), estradiol (E2), and SHBG. Preliminary results on efficacy (Minnemann, T., M. Schubert, D.
Hübler, A. Christoph, M. Oettel, M. Ernst, U. Mellinger, W.
Krone, and F. Jockenhövel, manuscript in preparation) (12,
13) and safety (14) of TU have already been presented
elsewhere.
Schubert et al. • TU in Hypogonadal Men
TABLE 1. Descriptive statistics of age, height, weight, and
BMI in the sample of 40 men with hypogonadism before start
of study treatment
Variable
Age (yr)
Mean
SD
Minimum
Maximum
Height (cm)
Mean
SD
Minimum
Maximum
Weight (kg)
Mean
SD
Minimum
Maximum
BMI (kg/m2)
Mean
SD
Minimum
Maximum
T (nmol/liter; screening 1)
Mean
SD
Minimum
Maximum
T (nmol/liter; screening 2)
Mean
SD
Minimum
Maximum
TU group
TE group
41.1
13.4
23.0
64.0
36.3
12.3
18.0
62.0
177.4
9.7
158.0
192.0
183.3
9.1
166.0
198.0
88.8
17.4
59.0
118.0
89.7
18.6
66.0
138.0
28.1
4.5
22.5
38.5
26.6
4.4
21.0
38.4
3.10
2.53
0.02
8.11
2.71
1.90
0.02
6.07
3.94
4.35
0.02
15.57
2.67
2.31
0.02
7.42
BMI, Body mass index.
Patients and Methods
Patients
The study protocol and the protocol amendments for the main study
and the follow-up studies were approved by the Ethics Committee of the
University and the State Medical Board, Cologne, Germany. All 40
patients gave their written informed consent at inclusion in the main
study. After completing the main study, all 20 patients of the TU group
and 16 patients of the TE group gave their consent to participate in the
follow-up study.
Forty men between the ages of 18 and 64 yr with serum T levels less
than 5 nmol/liter due to primary or secondary hypogonadism were
enrolled in the study. The men had been withdrawn from any T treatment for at least 18 wk before entering the study. At enrollment, all
subjects had no evidence of a severe physical or mental illness, as
deduced from medical history, physical examination, and analysis of
clinical laboratory parameters. There was no evidence of alcohol or drug
abuse or known contraindications for T treatment in any patient. At
randomization, there were no significant differences in the baseline
characteristics (Table 1) of the TU group (n ⫽ 20) and the TE group
(n ⫽ 20), regarding age (41.1 ⫾ 13.4 yr in TU group vs. 36.3 ⫾ 12.3 yr
in TE group), body mass index (28.1 ⫾ 4.5 kg/m2 in TU group vs. 26.6 ⫾
4.4 kg/m2 in TE group), and serum T levels (3.94 ⫾ 4.35 nmol/liter in
TU group vs. 2.67 ⫾ 2.31 nmol/liter in TE group). Five patients were
diagnosed with primary hypogonadism (Klinefelter’s syndrome,
anorchism, or testicular failure) in the TU group compared with seven
patients in the TE group. Secondary hypogonadism (hypothalamic or
pituitary disease or pituitary tumor) was present in 15 patients in the TU
group compared with 13 patients in the TE group.
FIG. 1. Flow diagram of the study protocol. For the first 30 wk of the
study, patients were randomized to receive im injections of either a
commercially available TE formulation (250 mg every 3 wk; n ⫽ 20)
or a long-acting TU formulation (1000 mg every 6 wk during the first
12 wk and, thereafter, 1000 mg every 9 wk; n ⫽ 20). After 30 wk of
therapy, all patients received 1000 mg TU im every 12 wk. *, In the
patients of the TE group, the interval between the first and second TU
injections was 8 wk.
Study design
The main study was designed as an open-label, active treatmentcontrolled, randomized, and prospective clinical trial. To ensure that the
patients met the inclusion criteria, screening visits were performed 42
and 21 d before randomization (for study design, see Fig. 1). In addition
to thorough physical, clinical, and andrological examinations, the following endocrine parameters were evaluated: serum levels of T, DHT,
E2, and SHBG, and parameters of liver function and bone metabolism,
Schubert et al. • TU in Hypogonadal Men
J Clin Endocrinol Metab, November 2004, 89(11):5429 –5434
5431
Statistical analysis
prostate-specific antigen (PSA), serum lipid profile, and hematological
indices.
For the 30 wk of the main study, patients were randomized to one of
the following treatments: TU patients (n ⫽ 20), 3 ⫻ 1000 mg TU in 4 ml
oily solution im at 6-wk intervals followed after 9 wk by 1 ⫻ 1000 mg
in 4 ml oily solution im for an additional 9 wk; and TE patients (n ⫽ 20),
10 ⫻ 250 mg TE in 1 ml oily solution im at 3-wk intervals.
Both the TE and TU formulations were manufactured by Jenapharm
GmbH & Co. KG (Jena, Germany). All im injections were injected into
the gluteus medius muscle, starting at d 0. Patients returned to the study
center every 3 wk during the main study for a clinical examination,
assessment of serum levels of T, DHT, E2, and SHBG, and assessment
of other study variables.
Patients who had already received TU injections (4 ⫻ 1000 mg at 6and 9-wk intervals, see first paragraph on this page) during the main
study were offered to continue their participation in the follow-up study
receiving the same dose at 12-wk intervals. Patients who had been on
TE treatment (10 ⫻ 250 mg TE at 3-wk intervals) were given the opportunity to switch over from the previous treatment to TU (1000 mg
TU). On initiation of TU therapy, a dosage interval of 8 wk between the
first two injections was observed to achieve loading. The further injections were given at intervals of 12 wk.
The following treatment regimens were established during the follow-up study: former TU patients, 8 ⫻ 1000 mg TU in 4 ml oily solution
at 12-wk intervals; and former TE patients, 2 ⫻ 1000 mg TU in 4 ml oily
solution at an 8-wk interval plus 6 ⫻ 1000 mg TU in 4 ml oily solution
at 12-wk intervals.
Baseline data for the individual study variables of interest during the
follow-up study were obtained at wk 30 of the main study (Table 2). In
the follow-up study, routine examinations and assessment of T, E2, and
SHBG were performed every 3 months.
In the main and the follow-up studies, the following efficacy and
safety parameters were assessed: efficacy of erythropoiesis (hemoglobin
and hematocrit); grip strength; well-being, mood, and sexual function;
serum levels of hormones (T, E2, and DHT; only during the main study)
and SHBG; bone mineral density; bone metabolism (calcium and osteocalcin in serum, calcium, pyridinoline, and deoxypyridinoline in
urine); body composition (weight, body mass index, waist-to-hip ratio,
skin-fold thickness, lean body mass, fat weight, and fat and lean proportion); lipid parameters (total cholesterol, low- and high-density lipoprotein cholesterols, very low-density lipoproteins, triglycerides, apolipoprotein A1 and B, lipoprotein (a); safety and adverse events; serum
levels of PSA; prostate size by transrectal ultrasonography; hematology
(erythrocytes, leukocytes, thrombocytes, and partial thromboplastin
time); liver function (alanine aminotransferase, aspartate aminotransferase, ␥-glutamyltransferase, abd total bilirubin); ferritin and iron; and
vital signs (blood pressure and heart rate). Additionally, the injection
side was monitored regularly. For safety reasons, serum levels of T and
PSA were closely monitored during the whole study.
Data were analyzed by descriptive statistical methods using SAS
version 6.12 (SAS Institute, Inc., Cary, NC). To compare the two groups
at baseline, the Wilcoxon rank sum test was used. Treatment-induced
changes in the parameters of interest were analyzed for each group using
the Wilcoxon signed rank test. All results are presented as mean ⫾ sd
unless stated otherwise.
Hormone assays
Serum T levels were measured by a coat-a-count total T solid-phase
I RIA (DPC Biermann, Bad Nauheim, Germany). The assay sensitivity
was limit of quantitation (LOQ) of 0.69 nmol/liter and limit of detection
(LOD) of 0.14 nmol/liter; the intraassay and interassay variability corresponded to 7.3 and 7.9%, respectively. Serum DHT concentrations
were measured by a coated-tube RIA, ACTIVE DHT (DSL, Sinsheim,
Germany). The assay sensitivity was LOQ of 0.086 nmol/liter and LOD
of 0.014 nmol/liter; the intraassay and interassay variability corresponded to 4.6 and 6.4%, respectively. Serum E2 was measured by
IMMULITE Estradiol, a solid-phase chemiluminescent enzyme immunoassay (DPC Biermann). The assay sensitivity was LOQ of 20 pg/ml
and LOD of 12 pg/ml; the intraassay and interassay variability corresponded to 9.3 and 10.6%, respectively. Serum levels of SHBG were
measured by IMMULITE SHBG, an immunometric assay (DPC Biermann). The assay sensitivity was LOD of 0.2 nmol/liter; the intraassay
and interassay variability corresponded to 6.5 and 8.7%, respectively.
All samples from each individual were measured in the same session
at the end of the main study and the follow-up study to avoid interassay
variability.
125
Results
Forty hypogonadal men were initially randomized to
one of the two treatment regimens (either TE, 250 mg every
3 wk; or TU, 1000 mg every 6 –9 wk). There were four
dropouts during the main study (all from the TE group;
three patients left the study for personal reasons and one
patient was excluded because inclusion criteria had been
violated). All 20 patients on TU and the remaining 16
patients on TE decided (and were considered by the investigator as suitable) to enter the follow-up study and to
receive TU injections at extended intervals of 12 wk. During the follow-up study, four patients dropped out (two
patients left the study for family-related reasons, one patient died in a car accident, and one patient moved
abroad). No patients discontinued treatment due to adverse events. No serious side effects were recorded during
TABLE 2. Serum levels of hormones (T, DHT, E2) and SHBG in patients with hypogonadism at baseline and after 30 wk of treatment
with TU (four doses of 1000 mg) or TE (10 doses of 250 mg) followed by eight TU injections in 12 weekly intervals (to convert estradiol to
picomoles per liter, multiply by 3.671)
Parameter [unit]
(reference range)
Patients [n]
T [nmol/liter] (10 –30)
Mean
SD
DHT [nmol/liter] (0.32–2.5)
Mean
SD
Estradiol [pg/ml] (20.4 – 44.9)
Mean
SD
SHBG [nmol/liter] (15–70)
Mean
SD
Main study TU
Baseline
20
3.94
4.35
0.316
0.264
wk 30
20
16.31
5.66
0.984
0.498
Main study TE
Baseline
20
wk 30
16
2.67
2.31
8.29
3.99
0.414
0.455
0.513
0.396
Follow-up study with eight TU doses
2nd TU injection
8th TU injection
36
32
16.46
7.99
16.17
4.99
21.55
6.91
29.63
8.02
23.07
4.96
27.46
9.33
26.82
12.30
22.85
4.94
30.01
20.57
25.14
12.43
29.80
14.17
25.96
11.05
25.34
11.37
25.81
11.23
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J Clin Endocrinol Metab, November 2004, 89(11):5429 –5434
Schubert et al. • TU in Hypogonadal Men
the entire period of the two studies. One serious adverse
event (convulsion at the time after the fourth TU injection
during the follow-up study in a patient with a 5-yr history
of similar symptoms) was assessed as not related to the
study drug, and the study treatment was continued in this
patient. Intramuscular injections were well tolerated by all
patients.
Serum T concentrations
At baseline, serum T concentrations did not significantly
differ between the two study groups, with endogenous levels
(mean ⫾ sd) of 2.67 ⫾ 2.31 nmol/liter in the TE group and
3.94 ⫾ 4.35 nmol/liter in the TU group (Table 1). These serum
T levels were markedly below the normal adult range of
10 –30 nmol/liter. Trough levels of serum T (Fig. 2) were
significantly higher in men receiving TU than in men receiving TE (14.14 ⫾ 4.48 vs. 8.02 ⫾ 3.66 nmol/liter, P ⬍ 0.0001,
and 16.31 ⫾ 5.66 vs. 8.29 ⫾ 3.99 nmol/liter, P ⬍ 0.0001, after
12 and 30 wk of therapy, respectively). Trough levels of
serum T were less than 10 nmol/liter in the TE group compared with trough levels between 10 and 20 nmol/liter in the
TU group and still rose (accumulating) when TU injections
were applied at intervals of 6 wk.
It must be pointed out that, due to the selected measurement time points, the graph for serum T levels in the TE
group in Fig. 2 only reflects T concentrations at the end of
each cycle, giving no information about T concentrations
between two TE injections. However, as known from previous studies of TE (1, 15), high supraphysiological serum T
concentrations are rapidly achieved and are maintained for
a few days. Subsequently, serum T levels decline and reach
subnormal levels within 3 wk, as confirmed at the measurement time points in the present study.
Slow accumulation of serum T after TU administration, as
detected at the end of the 6-wk intervals, was prevented by
extending the interval between the last two TU injections of
the main study to 9 wk.
During the follow-up study, injections of 1000 mg TU im
every 12 wk yielded stable mean T levels within the normal
range (value at the time of the eighth TU injection: 16.17 ⫾
4.99 nmol/liter; Fig. 2). The maximal trough T levels ranged
between 26.00 and 34.81 nmol/liter. Slightly elevated trough
values of T were found in few patients only.
FIG. 2. Serum T levels (mean ⫾ SEM) during the whole study period
(up to 30 months of therapy). After 30 wk of therapy, all patients
switched to TU injected every 12 wk.
FIG. 3. Serum DHT levels (mean ⫾ SEM) during the first 30 wk of
therapy. Blood samples were collected every 3 wk.
FIG. 4. Serum E2 levels (mean ⫾ SEM) during the whole study period
(up to 30 months of therapy). After 30 wk of therapy, all patients
switched to TU injected every 12 wk. Blood samples were collected
every 3 wk in the first phase of the study and every 12 wk during the
follow-up period (to convert E2 to picomoles per liter, multiply by
3.671).
Serum DHT levels
In both treatment groups, serum levels of DHT (Fig. 3)
increased in parallel to the serum T pattern (Fig. 2). During
the main study, mean DHT levels were significantly higher
in the TU group at wk 3, 9, 12, 15, 18, 24, 27, and 30 (P ⱕ 0.01)
and remained always within normal range of 0.32–2.5 nmol/
liter (Fig. 3). During the follow-up study, DHT was no longer
measured.
Serum E2 and SHBG levels
As expected, at the beginning of treatment, mean serum
levels of E2 in both treatment groups (Fig. 4) rose in parallel to the serum T levels (Fig. 2). During the comparative
part of the study, E2 values ranged from 82.7 ⫾ 13.7 to
143.6 ⫾ 36.2 pmol/liter in the TU group and from 83.4 ⫾
17.4 to 100.8 ⫾ 34.3 pmol/liter in the TE group. In the TU
group, E2 was slightly higher, reaching statistical significance compared with the TE group at wk 24 (P ⱕ 0.01).
During the follow-up study, mean serum E2 levels remained between 80.4 ⫾ 14.4 and 98.5 ⫾ 45.2 pmol/liter
(Fig. 4). Slight trends toward decrease of serum E2 levels
in individual patients led to normalization of initially elevated values in five patients. Slight decrease of E2 concentrations within the reference ranges became apparent
in 14 patients.
SHBG levels decreased slightly during the study period.
However, these changes were not significant because of large
interindividual variations (Fig. 5).
Schubert et al. • TU in Hypogonadal Men
FIG. 5. Serum SHBG levels (mean ⫾ SEM) during the whole study
period (up to 30 months of therapy). After 30 wk of therapy, all
patients switched to TU injected every 12 wk. Blood sampling was
performed every 3 wk in the first phase of the study and every 12 wk
during the follow-up period.
Discussion
Currently, injectable TE is the most frequently used T
formulation for T replacement in male hypogonadism (1, 5)
as well as in trials for male contraception (16). However,
injectable TE has pharmacokinetic disadvantages. It produces supraphysiological serum T levels during the first
days after injection with a steep decrease to the lower limit
of normal range within 10 –14 d (1, 5), causing discomfort to
the patients, which they experience as ups and downs in
vigor, mood, and sexual activity. Other T formulations, such
as T cypionate, with nearly identical pharmacokinetics (17)
do not offer substantial advantages (5). In the present study,
doses of 1000 mg TU for im injection were used. Single-dose
pharmacokinetic studies have proven that a dose of 1000 mg
TU in 4 ml castor oil does not result in supraphysiological
serum T levels but in prolonged action with a half-life
(mean ⫾ sem) of 33.9 ⫾ 4.9 d calculated from the T net values
(11). Based on the results of these studies, a computer simulation with the T half-life of 34 d was performed, resulting
in an optimal injection interval of 6 wk. Consequently, the
first multiple-dose pharmacokinetic phase II study of 1000
mg TU im was planned with 6-wk injection intervals (10).
The T measurement after the first injection confirmed the
results of the previously reported phase I study. However,
beginning with the second injection, T levels rose above
normal in five patients in the TU group in the first 3 wk. After
each following TU injection, more patients displayed supraphysiological T levels. These results suggest that an injection interval of 6 wk and longer might be sufficient to restore
normal T levels in hypogonadal men. Therefore, the injection
interval in the main study was extended to 9 wk after the
third injection and to 12 wk after the fifth injection in the
follow-up study. This interval was also confirmed in preliminary studies by Von Eckardstein and Nieschlag (18).
Compared with TE, TU has a prolonged half-life due to the
longer aliphatic and thus more hydrophobic side chain comprising 11 instead of seven carbon atoms.
Scrutiny of data reveals that, at all measurement points,
the mean serum T trough levels in the TE group were lower
compared with the TU group. The measurements in patients
receiving TE were always obtained at the end of the scheduled treatment interval, whereas in patients receiving TU, the
J Clin Endocrinol Metab, November 2004, 89(11):5429 –5434
5433
measurements were performed once in the middle and once
at the end of the required interval, thus explaining the markedly higher T levels measured in the TU group in wk 3 and
9. These results can be explained also by the higher total
exposure to TU compared with TE and the prolonged release
of T from the new formulation. After the third TU injection
(wk 12), a 9-wk interval was chosen before the fourth injection, which was further prolonged to 12 wk after the fifth
injection.
The trends in the changes in mean serum DHT and E2 levels
were similar during the two treatments. As expected, DHT
and E2 increased more markedly after TU administration.
The present results show that injecting 1000 mg TU im
every 12 wk is sufficient to maintain normal T levels in
hypogonadal men without causing major oscillations in serum T levels. We also demonstrate for the first time the
pharmacokinetics of a direct transition from a standard regimen with TE every 3 wk to the new TU preparation without
interruption. An initial load in the TE patients switching to
TU, assured by an interval of 8 wk between the first two TU
injections of 1000 mg, and followed by 12-wk intervals between the subsequent injections proved to be a suitable regimen to replace a short-acting formulation by the new TU
formulation.
There might be some concerns about the TU injection
volume of 4 ml. However, during the study period of
approximately 2 yr, we did not observe any local adverse
side effects in injection site, and none of the patients expressed any complaints. The TU preparation with a 4-ml
volume was tolerated as well as the TE injection with a
smaller volume. None of the patients opted to switch back to
TE during the follow-up period. Further prolongation of the
study, which is still ongoing, was welcomed by the patients.
Recently, a new transdermal preparation (gel) to deliver T,
which is a very convenient system with a good local tolerability, has been approved in the United States and Europe.
Daily application leads to stable T levels and confirmed clinical efficacy (8, 9). The present study shows that im TU given
at 12-wk intervals is an attractive formulation for T supplementation in hypogonadism. Only four im injections per year
without any further drug application in between might be
very appealing to active men requiring permanent substitution of T instead of daily gel administration. The first
multiple-dose pharmacokinetic studies using 1000 mg per
injection of this new TU formulation proposed an injection
interval of 6 wk. Here we demonstrate that injecting 1000 mg
TU every 12 wk is sufficient to maintain normal T and estrogen levels in hypogonadal men, without causing local or
systemic adverse side effects using this new formulation (19,
20). The only prerequisite consists of either two to three initial
loading doses at 6- and 9-wk intervals at the start of T substitution or two doses at 8-wk intervals when switching from
short-acting preparations to TU.
Acknowledgments
We thank our patients who made this investigations possible, and we
are very grateful for the excellent hormone analysis by Ms. Doris Vollmar. We thank Dr. Fricke, Jenapharm GmbH & Co. KG, for supplying
the TU and TE ampoules.
5434
J Clin Endocrinol Metab, November 2004, 89(11):5429 –5434
Received May 12, 2004. Accepted August 18, 2004.
Address all correspondence and requests for reprints to: Friedrich
Jockenhövel, M.D., Evangelisches Krankenhaus Herne, Wiescherstra␤e
24, 44623 Herne, Germany. E-mail: [email protected].
M.S. and T.M. contributed equally to this work.
Schubert et al. • TU in Hypogonadal Men
11.
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